The underlying quantitative variation in susceptibility to develop Alzheimer's disease (AD) is controlled by multiple genes, environmental factors, and metabolic signals. Importantly, some metabolic stimuli, like hypercholesterolemia, obesity, hyperinsulinemia and insulin resistance, follow certain dietary patterns and lifestyle, and are associated with increased risk of dementia and AD at advanced age. The detrimental effects of high fat diet (HFD) on cognitive performance and exacerbation of cerebral amyloidosis and amyloid angiopathy has been recently demonstrated in an animal model of AD. Equally important, exposure to some toxic environmental factors, such as drinking water arsenic (As), induces changes that are indistinguishable from, or coincide with pathological and clinical features of AD including: induced tau hyperphosphorylation, upregulation of amyloid precursor protein (APP); increased cardiovascular disease; enhanced brain inflammatory reactions, hyperinsulinemia in mice, and cognitive and memory deficits. It is completely unknown, however, whether HFD and environmental exposures combine to increase AD risk and disease progression. Emerging research and novel findings of epigenetic reprogramming inflicted by dietary agents or As exposure strongly suggest that induced changes in histone marks are retained throughout the life and accumulate to promote AD pathogenesis. Thus age dependent gene-environment interactions are critical for the development and progression of late onset AD (LOAD). It is therefore hypothesized that the combined impact of HFD and As on epigenetic chromatin modifications results in pathogenic tissue and organ-selective transcriptional activity that translates into increased risk of developing, accelerating or aggravating AD phenotypes. The objectives of the proposed research are: 1) In a well-established animal model for AD, to reveal organ specific changes in chromatin modifications in brain and liver, instigated by the collective effect of HFD and As exposure that produce genome wide pathogenic transcriptional activity, and 2) To reveal changes specific for AD phenotype (cognitive performance, amyloid deposition in brain parenchyma, metabolic abnormality and blood vessel wall remodeling) caused by combined exposures that result from identified changes in histone modifications. This goal will be achieved by accomplishing the following Specific Aims: Aim 1: To reveal the consequences of collective exposure to HFD and As on AD phenotype and lipid and glucose metabolism; and Aim 2: To assess changes in chromatin modifications in brain and liver induced by HFD and As in AD mice and to correlate specific changes in the epigenome to behavioral deficits and brain amyloidosis.